Cell-based phenotypic screening is increasingly being used for discovery of bioactive drug candidates. Discovering and validating protein targets for such bioactive small molecules in vivo often uses a combination of affinity enrichment and mass spectrometry methods. Such methods face several challenges. First, the moderate to weak binding between a small molecule and a protein target makes it hard to capture a target protein or protein complexes or biases the results towards high affinity interactors. Moreover, affinity enrichment methods typically use a solid support immobilized with the candidate small molecule. The kinetics of binding on solid surfaces is much slower when compared to solution-based kinetics, further decreasing the chance of capturing a target protein or protein complexes. Non-specific binding of proteins from cell lysate to the solid support results in high background that further complicates the identification of the cellular target using mass spectrometry (MS). Such methods often result in a large number of putative hits, making it necessary to run secondary screens to validate the potential targets. High-throughput validation assays for small molecule-protein interactions requires further development and optimization making it resource intensive process.